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Cite this: Chem. Commun., 2013, 49, 11230 Received 3rd September 2013, Accepted 15th October 2013
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Chemo-, regio-, and stereoselective iron-catalysed hydroboration of alkenes and alkynes†‡ Mark D. Greenhalgh and Stephen P. Thomas*
DOI: 10.1039/c3cc46727a www.rsc.org/chemcomm
The highly chemo-, regio-, and stereoselective synthesis of alkyland vinyl boronic esters with good functional group tolerance has been developed using in situ activation of a bench-stable iron(II) pre-catalyst and pinacolborane (16 examples, 45–95% yield, TOF up to 30 000 mol h
1
). The first iron-catalysed alkene hydro-
germylation is also reported.
Boronic acid derivatives have become ubiquitous in chemical synthesis. The facile stereospecific transformation of these diversely functionalised building blocks into a wide variety of functional groups has made them key intermediates in organic syntheses.1 Alkyl boronic esters are generally easy to isolate, purify and store, and can be used in a wide variety of transformations including Suzuki–Miyaura cross-coupling reactions for the generation sp3–sp2 C–C bonds (Fig. 1).2 Alkyl boronic esters are commonly prepared by reaction of alkyllithium and magnesium reagents with a boron source;1a however these methods are limited by poor functional-group tolerance and atom economy. Transition-metalcatalysed processes have the potential to overcome these problems. Direct borylation of alkanes using Rh, Ir, Ru, and Re catalysts under photochemical or thermal conditions has been reported,3 but these methods can suffer from forcing reaction conditions. Rhodium and iridium complexes are known to catalyse the addition of catecholand pinacolborane to olefins under mild conditions, and with good functional group tolerance.4 Many regio- and enantioselective examples have been reported,4,5 however competitive dehydroboration,6 and the relative instability of catecholborane5b,7 can effect synthetic utility. The copper-catalysed synthesis of alkyl boronic esters from primary and secondary alkyl halides has been reported with good functional group tolerance,2e however long reaction times, excess B2pin2, and relatively high catalyst loadings were required. Iron offer significant advantages as a catalyst due to its low toxicity, low cost, natural abundance and sustainable long-term
School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh, EH9 3JJ, UK. E-mail: stephen.thomas.ed.ac.uk † Celebrating 300 years of Chemistry at Edinburgh. ‡ Electronic supplementary information (ESI) available: Experimental details, product characterisation and NMR spectra. See DOI: 10.1039/c3cc46727a
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Chem. Commun., 2013, 49, 11230--11232
Fig. 1
Selected synthetic transformations of alkylboronic esters.1,2
commercial availability.8 Ritter reported the 1,4-hydroboration of terminal 1,3-dienes using an iron(II) iminopyridine complex, which was reduced to an active catalyst in situ using elemental magnesium.9 Good to excellent regioselectivity and excellent stereoselectively were demonstrated. Enthaler has shown that Fe2(CO)9 can catalyse the hydroboration of terminal and internal alkynes with pinacolborane to give vinyl boronic esters in up to 99 : 1 dr.10 Recently, Huang11 and Chirik12 have reported the ironcatalysed hydroboration of alkenes using pinacolborane. Huang found that a bipyridyl phosphine iron(II) complex activated with sodium triethylborohydride produced a highly active catalyst for the hydroboration of terminal, and 1,1-disubstituted alkenes. Chirik reported that bis(imimo)pyridine iron(0) bis(dinitrogen) complexes13 would catalyse the addition of pinacolborane to terminal-, 1,1- and 1,2-disubstituted alkenes. Functional group tolerance has been demonstrated for tertiary amine, silyl, ether, acetal and tosyl-protected alcohol substrates; however both methods suffer from the use of highly air- and moisture sensitive pre-catalysts. Herein we report the iron-catalysed hydroboration of alkenes and alkynes using a bench stable iron(II) pre-catalyst and pinacolborane to give alkyl and vinyl boronic esters directly. Iron(II) salts are reduced to highly active, low-valent species by reaction with a Grignard reagent,14 which we speculated may provide simple access to catalysts for hydroboration. Using 4-phenylbutene as a model substrate, initial studies focussed on hydroboration using pinacolborane (HBpin), bis(imino)pyridine iron(II) complex [1-FeCl2]15 (5 mol%), and tolylmagnesium This journal is
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Table 1 agenta
ChemComm
Optimisation of iron-catalysed hydroboration: solvent and activating
Entry [Fe] (mol%) Activating agent (mol%) Solvent
Yieldb (%)
1 2 3 4 5c 6c 7d 8e
18 92 91 52 90 89 92 94 f
5 5 5 5 1 1 1 0.2
TolMgBr (5) TolMgBr (10) TolMgBr (15) TolMgBr (25) EtMgBr (3) TolMgBr (3) n-BuLi (3) n-BuLi (0.6)
THF THF THF THF THF THF Toluene ‘Solvent-free’
Table 2 Iron-catalysed hydroboration of olefins: scope and functional group tolerancea
a Conditions: 4-phenylbutene (0.7 mmol), [1-FeCl2] (5 mol%), activating agent (x mol%), HBpin (1.1 equiv.), solvent (0.25 M), 1 h, r.t. b Yield determined by 1H NMR of the crude reaction mixture using 1,3,5trimethoxybenzene as internal standard. c FeCl2 (1 mol%) and 1 (1 mol%) complexed in situ in place of [1-FeCl2]. d [1-FeCl2] (1 mol%). e Conditions: 4-phenylbutene (7.33 mmol), [1-FeCl2] (0.2 mol%), n-BuLi (0.6 mol%), HBpin (1.1 equiv.), 1 min, r.t. f Isolated yield (1.80 g).
bromide (TolMgBr) as activating agent in tetrahydrofuran. Using 5 mol% TolMgBr gave only a low yield of the linear boronic ester 3a (Table 1, entry 1); however 10 and 15 mol% TolMgBr gave the linear boronic ester 3a directly in excellent yield and complete regioselectivity (entries 2 and 3). Use of 25 mol% TolMgBr, led to a decreased yield of 3a (entry 4). The system was equally active using 1 mol% pre-catalyst, which could be prepared in situ by simple combination of FeCl2 (1 mol%) and free bis(imino)pyridine ligand 1 (1 mol%) prior to the addition of substrate and activator. Activation with EtMgBr (3 mol%) gave equal results to that using TolMgBr (entries 5 and 6). To demonstrate increased industrial applicability, the hydroboration was developed to operate in both toluene and under ‘solvent-free’ conditions.16 A suspension of iron complex [1-FeCl2] (1 mol%) in either toluene, or neat alkene,17 could be activated for alkene hydroboration by the addition of n-BuLi (3 mol%) (entry 7). Using ‘solvent-free’ reaction conditions, the gram-scale hydroboration of 4-phenylbutene 2a with pinacolborane was complete within 1 minute using just 0.2 mol% catalyst, corresponding to a catalyst turnover frequency of 30 000 mol h 1 (entry 8). To the best of our knowledge this represents the most efficient iron catalyst reported to date for the hydroboration of olefins. Activation (reduction) of the iron(II) pre-catalyst [1-FeCl2] using TolMgBr allowed the average oxidation state of iron to be calculated by quantifying the formation of bitolyl. Maximum catalytic activity corresponded to an average oxidation state of iron(I).18,19 The functional group tolerance of the hydroboration was then investigated using the in situ complexation of FeCl2 (1 mol%) and 1 (1 mol%) in tetrahydrofuran, and activation with EtMgBr (3 mol%) (Table 2). Aryl fluoride, chloride and bromide substituted alkenes 2b–d were tolerated under the reaction conditions giving linear boronic esters 3b–d in excellent yield and This journal is
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a
Conditions: olefin (0.7 mmol), FeCl2 (1 mol%), 1 (1 mol%), EtMgBr (3 mol%), HBpin (1.1 equiv.), THF (0.25 M), 1 h, r.t. b Yield determined by 1H NMR of the crude reaction mixture using 1,3,5-trimethoxybenzene as internal standard, isolated yield given in parentheses. c TolMgBr (105 mol%) used. d Product isolated as the diol following oxidation. e FeCl2 (5 mol%), 1 (5 mol%), EtMgBr (15 mol%) used. f Conditions: olefin (0.7 mmol), [1-FeCl2] (1 mol%), n-BuLi (3 mol%), HBpin (1.1 equiv.), 1 h, r.t.
regioselectivity, with no cleavage of the aryl-halide bond observed.14b,20 Unprotected amine 2e and alcohol 2f were successfully hydroborated, and gave linear boronic esters 3e and 3f with complete control of regiochemistry and in excellent and moderate yield, respectively. Substrates containing more than one unsaturated group were then investigated. Ester substituted alkene 2g was chemoselectively hydroborated in excellent yield and regioselectivity, with no observed C–O bond cleavage,21 or ester reduction. Secondary amide 2h reacted to give only a moderate yield of the linear boronic ester 3h, along with unreacted starting material, suggesting catalyst deactivation. Aldimine substituted alkene 2i was chemoselectively hydroborated at the alkene, with less than 10% aldimine reduction observed. 4-Vinylcyclohexene 2j was also chemoselectively hydroborated at the terminal alkene giving linear boronic ester 3j in excellent yield and regioselectivity, with the internal alkene intact. Using ‘solvent-free’ reaction conditions, 1,1- and 1,2-disubstituted alkenes were also suitable substrates for hydroboration. Boronic esters 3k–m were isolated in good to excellent yield, and in the case of 3k and 3l with perfect regioselectivity for the linear boronic ester product. Chem. Commun., 2013, 49, 11230--11232
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Scheme 1
Iron-catalysed hydrogermylation of styrene.
The developed methodology was also applied to the hydroboration of alkynes. (Z)-Vinyl boronic esters 5a and 5b were stereoselectively synthesised in excellent yield within one hour, with no observed anti-addition of pinacolborane, representing the most active and stereoselective iron catalyst reported for the hydroboration of alkynes. Finally, the developed methodology was applied to the hydrogermylation of styrene using commercially available triethylgermanium hydride, giving the linear hydrogermylation product 6 in 86% isolated yield and with complete control of regiochemistry (Scheme 1). To the best of our knowledge, this is the first example of an iron-catalysed alkene hydrogermylation,22 but more significantly illustrates the generality of this iron catalyst in the activation of small molecules, and indicates the potential for further synthetic applications. In summary, we have reported a highly functional group tolerant, operationally simple, chemo-, regio- and stereoselective iron-catalysed hydroboration of alkenes and alkynes, which uses just 1 mol% iron catalyst [FeCl2 (1 mol%), ligand 1 (1 mol%)] and 1.1 equivalents of pinacolborane at room temperature. All reagents used were commercially available, easy to handle and store, and the active iron catalyst was generated in situ. Terminal, 1,1- and 1,2-disubstituted aryl and alkyl alkenes and alkynes bearing an unprecedented diversity of functional groups were successfully hydroborated with excellent control of all aspects of selectivity (chemo, regio and stereochemistry). The methodology was shown to operate under ‘solvent-free’ conditions and on gram-scale, improving industrial applicability and the ease of product isolation. Preliminary mechanistic experiments suggest that an iron(I) catalyst may be formed under the reaction conditions. The use of an in situ generated iron catalyst greatly simplifies practical requirements, and should allow the non-expert to fully utilise this synthetic methodology. M.D.G. thanks the University of Edinburgh for the provision of a studentship. S.P.T. thanks the Royal Society for generous funding.
Communication
3 4
5
6
7 8 9 10 11 12 13
14
15
16 17 18 19
Notes and references 1 (a) H. C. Brown, Organic Synthesis via Boranes, Wiley, New York, 1975; (b) H. C. Brown and B. Singaram, Pure Appl. Chem., 1987, 59, 879; (c) Science of Synthesis: Vol. 6, Boron Compounds, ed. D. E. Kaufmann and D. S. Matteson, Georg Thieme Verlag, StuttgartNew York, 2004; (d) Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, ed. D. G. Hall, Wiley-VCH, Weinheim, 2005; (e) S. N. Mlynarski, A. S. Karns and J. P. Morken, J. Am. Chem. Soc., 2012, 134, 16449; ( f ) J. L. Stymiest, V. Bagutski, R. M. French and V. K. Aggarwal, Nature, 2008, 456, 778; ( g) V. Bagutski, R. M. French and V. K. Aggarwal, Angew. Chem., Int. Ed., 2010, 49, 5142. 2 For reviews see: (a) H. Doucet, Eur. J. Org. Chem., 2008, 2013; (b) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011,
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20
21 22
111, 1417; For selected examples see: (c) M. Sato, N. Miyaura and A. Suzuki, Chem. Lett., 1989, 1405; (d) S. D. Dreher, S.-E. Lim, D. L. Sandrock and G. A. Molander, J. Org. Chem., 2009, 74, 3626; (e) C.-T. Yang, Z.-Q. Zhang, H. Tajuddin, C.-C. Wu, J. Liang, J.-H. Liu, Y. Fu, P. G. Steel, T. B. Marder and L. Liu, Angew. Chem., Int. Ed., 2012, 51, 528. (a) H. Chen, S. Schlecht, T. C. Semple and J. F. Hartwig, Science, 2000, 287, 1995; (b) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890. (a) K. Burgess and M. J. Ohlmeyer, Chem. Rev., 1991, 91, 1179; (b) I. Beletskaya and A. Pelter, Tetrahedron, 1997, 53, 4957; (c) N. Miyaura, in Catalytic Heterofunctionalization, ed. A. Togni ¨tzmacher, Wiley-VCH, Weinheim, 2001, ch. 1, pp. 1–45. and H. Gru (a) T. Hayashi, in Comprehensive Asymmetric Catalysis, ed. E. C. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, ch. 9, pp. 351–367; (b) C. M. Crudden and D. Edwards, Eur. J. Org. Chem., 2003, 4695; (c) J. M. Brown, in Modern Rhodium-Catalyzed Organic Reactoins, ed. P. A. Evans, Wiley-VCH, Weinheim, 2005, ch. 2. pp. 33–54. (a) K. Burgess, W. A. van der Donk, S. A. Westcott, T. B. Marder, R. T. Baker and J. C. Calabrese, J. Am. Chem. Soc., 1992, 114, 9350; (b) S. A. Westcott and T. B. Marder, Organometallics, 1993, 12, 975; (c) R. T. Baker, J. C. Calabrese, S. A. Westcott, P. Nguyen and T. B. Marder, J. Am. Chem. Soc., 1993, 115, 4367. S. A. Westcott, H. P. Blom and T. B. Marder, Inorg. Chem., 1993, 32, 2175. (a) S. Enthaler, K. Junge and M. Beller, Angew. Chem., Int. Ed., 2008, 47, 3317; (b) BGS (2012a), Risk list 2012, Nottingham, U.K., British Geological Survey. J. Y. Wu, B. Moreau and T. Ritter, J. Am. Chem. Soc., 2009, 131, 12915. M. Haberberger and S. Enthaler, Chem.–Asian J., 2013, 8, 50. L. Zhang, D. Peng, X. Leng and Z. Huang, Angew. Chem., Int. Ed., 2013, 52, 3676. J. V. Obligacion and P. J. Chirik, Org. Lett., 2013, 15, 2680. (a) S. C. Bart, E. Lobkovsky and P. J. Chirik, J. Am. Chem. Soc., 2004, 126, 13794; (b) S. K. Russell, J. M. Darmon, E. Lobkovsky and P. J. Chirik, Inorg. Chem., 2010, 49, 2782; (c) A. M. Tondreau, C. C. H. Atienza, K. J. Weller, S. A. Nye, K. M. Lewis, J. G. P. Delis and P. J. Chirik, Science, 2012, 335, 567. Grignard reagents are known to reduce Fe(II) salts to low-valent, highly reactive species, see: (a) B. Bogdanovic and M. Schwickardi, ¨rstner, R. Martin, Angew. Chem., Int. Ed., 2000, 39, 4610; (b) A. Fu H. Krause, G. Seidel, R. Goddard and C. W. Lehmann, J. Am. Chem. Soc., 2008, 130, 8773. For Fe(II) complex see: (a) M. S. Brookhart and B. L. Small, Wo. Pat., 1998030612 A1, 1998; (b) G. J. P. Britovsek, V. C. Gibson and S. K. Spitzmesser, Wo. Pat., 2000015646 A1, 2000; (c) R. Schmidt, M. B. Welch, R. D. Knudsen, S. Gottfried and H. G. Alt, J. Mol. Catal. A: Chem., 2004, 222, 9. For Fe(0) analogue see ref. 13b. (a) R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854. In situ complexation of FeCl2 and 1 in toluene or neat alkene not possible due to the low solubility of the Fe(II) complex. See ESI‡ for further details. For recent examples of Fe(I) in cross-coupling reactions see: ¨m, P.-F. Larsson, C. Johansson and P.-O. (a) J. Kleimark, A. Hedstro ¨m, U. Bollmann, Norrby, ChemCatChem, 2009, 1, 152; (b) A. Hedstro J. Bravidor and P.-O. Norrby, Chem.–Eur. J., 2011, 17, 11991; ¨m and (c) J. Kleimark, P.-F. Larsson, P. Emany, A. Hedstro P.-O. Norrby, Adv. Synth. Catal., 2011, 354, 448; (d) C. J. Adams, et al., J. Am. Chem. Soc., 2012, 134, 10333; (e) R. B. Bedford, E. Carter, P. M. Cogswell, N. J. Gower, M. F. Haddow, J. N. Harvey, D. M. Murphy, E. C. Neeve and J. Nunn, Angew. Chem., Int. Ed., 2013, ´n-Ceinos, F. Tato, E. Bun ˜uel, P. Calle and 52, 1285; ( f ) M. Guisa ´rdenas, Chem. Sci., 2013, 4, 1098. D. J. Ca (a) T. Hatakeyama, Y. Kondo, Y. Fujiwara, H. Rakaya, S. Ito, E. Nakamura and M. Nakamura, Chem. Commun., 2009, 1216; (b) W. M. Czaplik, S. Grupe, M. Mayer and A. Jacobi von Wangelin, Chem. Commun., 2010, 46, 6350. R. J. Trovitch, E. Lobkovsky, M. W. Bouwkamp and P. J. Chirik, Organometallics, 2008, 27, 6264. For Fe-catalysed hydrogermylation of alkynes see: M. Itazaki, M. Kamitani and H. Nakazawa, Chem. Commun., 2011, 47, 7854.
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COMMUNICATION
Cite this: Chem. Commun., 2013, 49, 11230 Received 3rd September 2013, Accepted 15th October 2013
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Chemo-, regio-, and stereoselective iron-catalysed hydroboration of alkenes and alkynes†‡ Mark D. Greenhalgh and Stephen P. Thomas*
DOI: 10.1039/c3cc46727a www.rsc.org/chemcomm
The highly chemo-, regio-, and stereoselective synthesis of alkyland vinyl boronic esters with good functional group tolerance has been developed using in situ activation of a bench-stable iron(II) pre-catalyst and pinacolborane (16 examples, 45–95% yield, TOF up to 30 000 mol h
1
). The first iron-catalysed alkene hydro-
germylation is also reported.
Boronic acid derivatives have become ubiquitous in chemical synthesis. The facile stereospecific transformation of these diversely functionalised building blocks into a wide variety of functional groups has made them key intermediates in organic syntheses.1 Alkyl boronic esters are generally easy to isolate, purify and store, and can be used in a wide variety of transformations including Suzuki–Miyaura cross-coupling reactions for the generation sp3–sp2 C–C bonds (Fig. 1).2 Alkyl boronic esters are commonly prepared by reaction of alkyllithium and magnesium reagents with a boron source;1a however these methods are limited by poor functional-group tolerance and atom economy. Transition-metalcatalysed processes have the potential to overcome these problems. Direct borylation of alkanes using Rh, Ir, Ru, and Re catalysts under photochemical or thermal conditions has been reported,3 but these methods can suffer from forcing reaction conditions. Rhodium and iridium complexes are known to catalyse the addition of catecholand pinacolborane to olefins under mild conditions, and with good functional group tolerance.4 Many regio- and enantioselective examples have been reported,4,5 however competitive dehydroboration,6 and the relative instability of catecholborane5b,7 can effect synthetic utility. The copper-catalysed synthesis of alkyl boronic esters from primary and secondary alkyl halides has been reported with good functional group tolerance,2e however long reaction times, excess B2pin2, and relatively high catalyst loadings were required. Iron offer significant advantages as a catalyst due to its low toxicity, low cost, natural abundance and sustainable long-term
School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh, EH9 3JJ, UK. E-mail: stephen.thomas.ed.ac.uk † Celebrating 300 years of Chemistry at Edinburgh. ‡ Electronic supplementary information (ESI) available: Experimental details, product characterisation and NMR spectra. See DOI: 10.1039/c3cc46727a
11230
Chem. Commun., 2013, 49, 11230--11232
Fig. 1
Selected synthetic transformations of alkylboronic esters.1,2
commercial availability.8 Ritter reported the 1,4-hydroboration of terminal 1,3-dienes using an iron(II) iminopyridine complex, which was reduced to an active catalyst in situ using elemental magnesium.9 Good to excellent regioselectivity and excellent stereoselectively were demonstrated. Enthaler has shown that Fe2(CO)9 can catalyse the hydroboration of terminal and internal alkynes with pinacolborane to give vinyl boronic esters in up to 99 : 1 dr.10 Recently, Huang11 and Chirik12 have reported the ironcatalysed hydroboration of alkenes using pinacolborane. Huang found that a bipyridyl phosphine iron(II) complex activated with sodium triethylborohydride produced a highly active catalyst for the hydroboration of terminal, and 1,1-disubstituted alkenes. Chirik reported that bis(imimo)pyridine iron(0) bis(dinitrogen) complexes13 would catalyse the addition of pinacolborane to terminal-, 1,1- and 1,2-disubstituted alkenes. Functional group tolerance has been demonstrated for tertiary amine, silyl, ether, acetal and tosyl-protected alcohol substrates; however both methods suffer from the use of highly air- and moisture sensitive pre-catalysts. Herein we report the iron-catalysed hydroboration of alkenes and alkynes using a bench stable iron(II) pre-catalyst and pinacolborane to give alkyl and vinyl boronic esters directly. Iron(II) salts are reduced to highly active, low-valent species by reaction with a Grignard reagent,14 which we speculated may provide simple access to catalysts for hydroboration. Using 4-phenylbutene as a model substrate, initial studies focussed on hydroboration using pinacolborane (HBpin), bis(imino)pyridine iron(II) complex [1-FeCl2]15 (5 mol%), and tolylmagnesium This journal is
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Table 1 agenta
ChemComm
Optimisation of iron-catalysed hydroboration: solvent and activating
Entry [Fe] (mol%) Activating agent (mol%) Solvent
Yieldb (%)
1 2 3 4 5c 6c 7d 8e
18 92 91 52 90 89 92 94 f
5 5 5 5 1 1 1 0.2
TolMgBr (5) TolMgBr (10) TolMgBr (15) TolMgBr (25) EtMgBr (3) TolMgBr (3) n-BuLi (3) n-BuLi (0.6)
THF THF THF THF THF THF Toluene ‘Solvent-free’
Table 2 Iron-catalysed hydroboration of olefins: scope and functional group tolerancea
a Conditions: 4-phenylbutene (0.7 mmol), [1-FeCl2] (5 mol%), activating agent (x mol%), HBpin (1.1 equiv.), solvent (0.25 M), 1 h, r.t. b Yield determined by 1H NMR of the crude reaction mixture using 1,3,5trimethoxybenzene as internal standard. c FeCl2 (1 mol%) and 1 (1 mol%) complexed in situ in place of [1-FeCl2]. d [1-FeCl2] (1 mol%). e Conditions: 4-phenylbutene (7.33 mmol), [1-FeCl2] (0.2 mol%), n-BuLi (0.6 mol%), HBpin (1.1 equiv.), 1 min, r.t. f Isolated yield (1.80 g).
bromide (TolMgBr) as activating agent in tetrahydrofuran. Using 5 mol% TolMgBr gave only a low yield of the linear boronic ester 3a (Table 1, entry 1); however 10 and 15 mol% TolMgBr gave the linear boronic ester 3a directly in excellent yield and complete regioselectivity (entries 2 and 3). Use of 25 mol% TolMgBr, led to a decreased yield of 3a (entry 4). The system was equally active using 1 mol% pre-catalyst, which could be prepared in situ by simple combination of FeCl2 (1 mol%) and free bis(imino)pyridine ligand 1 (1 mol%) prior to the addition of substrate and activator. Activation with EtMgBr (3 mol%) gave equal results to that using TolMgBr (entries 5 and 6). To demonstrate increased industrial applicability, the hydroboration was developed to operate in both toluene and under ‘solvent-free’ conditions.16 A suspension of iron complex [1-FeCl2] (1 mol%) in either toluene, or neat alkene,17 could be activated for alkene hydroboration by the addition of n-BuLi (3 mol%) (entry 7). Using ‘solvent-free’ reaction conditions, the gram-scale hydroboration of 4-phenylbutene 2a with pinacolborane was complete within 1 minute using just 0.2 mol% catalyst, corresponding to a catalyst turnover frequency of 30 000 mol h 1 (entry 8). To the best of our knowledge this represents the most efficient iron catalyst reported to date for the hydroboration of olefins. Activation (reduction) of the iron(II) pre-catalyst [1-FeCl2] using TolMgBr allowed the average oxidation state of iron to be calculated by quantifying the formation of bitolyl. Maximum catalytic activity corresponded to an average oxidation state of iron(I).18,19 The functional group tolerance of the hydroboration was then investigated using the in situ complexation of FeCl2 (1 mol%) and 1 (1 mol%) in tetrahydrofuran, and activation with EtMgBr (3 mol%) (Table 2). Aryl fluoride, chloride and bromide substituted alkenes 2b–d were tolerated under the reaction conditions giving linear boronic esters 3b–d in excellent yield and This journal is
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a
Conditions: olefin (0.7 mmol), FeCl2 (1 mol%), 1 (1 mol%), EtMgBr (3 mol%), HBpin (1.1 equiv.), THF (0.25 M), 1 h, r.t. b Yield determined by 1H NMR of the crude reaction mixture using 1,3,5-trimethoxybenzene as internal standard, isolated yield given in parentheses. c TolMgBr (105 mol%) used. d Product isolated as the diol following oxidation. e FeCl2 (5 mol%), 1 (5 mol%), EtMgBr (15 mol%) used. f Conditions: olefin (0.7 mmol), [1-FeCl2] (1 mol%), n-BuLi (3 mol%), HBpin (1.1 equiv.), 1 h, r.t.
regioselectivity, with no cleavage of the aryl-halide bond observed.14b,20 Unprotected amine 2e and alcohol 2f were successfully hydroborated, and gave linear boronic esters 3e and 3f with complete control of regiochemistry and in excellent and moderate yield, respectively. Substrates containing more than one unsaturated group were then investigated. Ester substituted alkene 2g was chemoselectively hydroborated in excellent yield and regioselectivity, with no observed C–O bond cleavage,21 or ester reduction. Secondary amide 2h reacted to give only a moderate yield of the linear boronic ester 3h, along with unreacted starting material, suggesting catalyst deactivation. Aldimine substituted alkene 2i was chemoselectively hydroborated at the alkene, with less than 10% aldimine reduction observed. 4-Vinylcyclohexene 2j was also chemoselectively hydroborated at the terminal alkene giving linear boronic ester 3j in excellent yield and regioselectivity, with the internal alkene intact. Using ‘solvent-free’ reaction conditions, 1,1- and 1,2-disubstituted alkenes were also suitable substrates for hydroboration. Boronic esters 3k–m were isolated in good to excellent yield, and in the case of 3k and 3l with perfect regioselectivity for the linear boronic ester product. Chem. Commun., 2013, 49, 11230--11232
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Scheme 1
Iron-catalysed hydrogermylation of styrene.
The developed methodology was also applied to the hydroboration of alkynes. (Z)-Vinyl boronic esters 5a and 5b were stereoselectively synthesised in excellent yield within one hour, with no observed anti-addition of pinacolborane, representing the most active and stereoselective iron catalyst reported for the hydroboration of alkynes. Finally, the developed methodology was applied to the hydrogermylation of styrene using commercially available triethylgermanium hydride, giving the linear hydrogermylation product 6 in 86% isolated yield and with complete control of regiochemistry (Scheme 1). To the best of our knowledge, this is the first example of an iron-catalysed alkene hydrogermylation,22 but more significantly illustrates the generality of this iron catalyst in the activation of small molecules, and indicates the potential for further synthetic applications. In summary, we have reported a highly functional group tolerant, operationally simple, chemo-, regio- and stereoselective iron-catalysed hydroboration of alkenes and alkynes, which uses just 1 mol% iron catalyst [FeCl2 (1 mol%), ligand 1 (1 mol%)] and 1.1 equivalents of pinacolborane at room temperature. All reagents used were commercially available, easy to handle and store, and the active iron catalyst was generated in situ. Terminal, 1,1- and 1,2-disubstituted aryl and alkyl alkenes and alkynes bearing an unprecedented diversity of functional groups were successfully hydroborated with excellent control of all aspects of selectivity (chemo, regio and stereochemistry). The methodology was shown to operate under ‘solvent-free’ conditions and on gram-scale, improving industrial applicability and the ease of product isolation. Preliminary mechanistic experiments suggest that an iron(I) catalyst may be formed under the reaction conditions. The use of an in situ generated iron catalyst greatly simplifies practical requirements, and should allow the non-expert to fully utilise this synthetic methodology. M.D.G. thanks the University of Edinburgh for the provision of a studentship. S.P.T. thanks the Royal Society for generous funding.
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